Cannabis use disorder (CUD), common in patients with schizophrenia (SCHIZ), contributes greatly to the morbidity of SCHIZ. Although typical antipsychotic medications do not control cannabis use in these patients, preliminary data from our group and others suggest that the atypical antipsychotic drug clozapine (CLOZ) may limit cannabis use in patients with SCHIZ much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotics risperidone (RISP) or olanzapine (OLAN). We are conducting a NIDA funded (DA 13196) 12-week randomized clinical trial to further assess CLOZ effects on cannabis use, clinical symptoms/quality of life in patients with schizophrenia and comorbid CUD, as compared to patients treated with RISP or OLAN. This R21 application proposes an "add-on" functional MRI (fMRI) pilot study of brain reward circuitry to this "base" study. We have previously hypothesized that CLOZ (but not RISP, OLAN or typical antipsychotics) will help normalize dysfunctional brain reward circuits that may underlie comorbid cannabis use in SCHIZ. In this "add-on" study, a sub-sample of 24 RISP treated patients from the "base" study will undergo an fMRI monetary reward probe of brain reward circuit while being treated with RISP. In the "base" study, half of these patients will be randomized to CLOZ and half will remain on RISP for the 12- week clinical trial; in the "add-on" study, all patients will have repeat fMRI reward circuit testing at 12 weeks, and a matched group of normal controls will also be tested, twice (at recruitment and at 12 weeks). The proposed study will attempt to identify a potential imaging biomarker" of the action of CLOZ (as compared to RISP) on brain reward circuits. The overarching hypothesis for this research is that patients treated with RISP will demonstrate deficiencies in response to a brain reward circuit probe compared to normal controls and that these deficiencies will be normalized in patients treated with CLOZ. We also predict that there will be a relationship between the normalization of brain reward circuit response and decrease in cannabis use by patients. We expect this research to lead to an efficient method for testing medications that putatively may decrease cannabis use in SCHIZ. This is of great importance because, despite the benefits of CLOZ, its toxicity discourages many clinicians from using it. Finding new medications, safer than CLOZ, that may be able to limit cannabis use In patients with SCHIZ is thus of considerable public health relevance.